It is a nobrainer of course to state that most diseases are somehow linked through a common connection which is either directly or indirectly environmental or exogenous (food, air, water, society), or endogenous. (genetic malfunction). In the latter case things may be more complicated than they appear on the surface. One can expect there to be a very intimate interplay between all parts and systems of the body, and what's more. the interdependence is most likely under close supervision of -what Dr Douglas Fields calls- our super-brain: the glia connectome and especially the microglia. As long as we continue to focus on separate elements, without taking into account the upstream and downstream effects, we will have a hard time arriving at a comprehensive approach to health in all its multifaceted, multifunctional, but also multifactorial aspects. (1)

The difficulty in analyzing everything at play in for instance neurodegenerative diseases is a prime example of how focusing on one visible, or measurable symptom -amyloid plaque- can easily lead one in a direction which may turn out a waste of time and energy, and may even for years to come, prevent one from finding a solution. The history of scientific endeavour is littered with examples of considering symptoms as the cause.

In order to understand anything at all about how neurodegenerative diseases could develop, we need to know how the ''glia connectome'' works.

Fields: “I believe that the present state of affairs in the exploration of neural networks and integrated understanding how the neural connectome works, though undoubtedly important, will not deliver any further insight in the development of neuro-degenerative diseases if the non-electrical part of the brain is left out of the picture.”

While the human brain contains roughly 100 billion neurons, it contains billions more glia, the non-electrical cells that are able to connect and transmit wireless.

Today it may sound a bit quaint that these glia were simply called connective tissue in the mid 1800's.

In fact there are three different kinds of glial cells: Astrocytes, oligodendrocytes and microglia.

Astrocytes are in tight cahoots with the neurons and are responsible for assuring an adequate supply of nutrients. Studies on neuron cultures from rodent central nervous systems have shown that neurons depend upon astrocytes for their supply of cholesterol. Neurons critically need cholesterol, both in the synapse and in the myelin sheath, in order to successfully transmit their signals, and also as a first line of defence against invasive microbes. Cholesterol is so important to the brain that astrocytes are able to synthesize it from basic ingredients, a skill not found in most cell types. They also supply the neurons with fatty acids, and they are able to take in short chain fatty acids and combine them to form the longer-chain types of fatty acids that are especially prominent in the brain, and then deliver them to neighbouring neurons and to the cerebrospinal fluid.

Oligodendrocytes keep the myelin sheath healthy. They synthesize a special sulphur-containing fatty acid, known as sulfatide, from other fatty acids supplied to them by the cerebrospinal fluid. It is now well known that the myelin sheath insulating layer is known to be defective in Alzheimer's.

Note: Sulfatide, a class of sulfolipids, specifically a class of sulfoglycolipids synthesized primarily starting in the endoplasmic reticulum and ending in the Golgi apparatus where ceramide is converted to galactocerebroside and later sulfated to make sulfatide. Of all of the myelin galactolipids, one fifth is sulfatide. Sulfatide is primarily found on the extracellular leaflet of the myelin plasma membrane produced by the oligodendrocytes. This is also where the ApoE (apolipoprotein) comes in. ApoE is needed in the maintenance of sulfatide. Throughout a person's life, the myelin sheath has to be constantly maintained and repaired. This is something that researchers are only beginning to appreciate, but two related properties of Alzheimer's are poor quality myelin sheath alongside a drastically reduced concentration of fatty acids and cholesterol in the cerebrospinal fluid.(Mulder et.al) (33)

Sulfatide has been shown to be essential for the maintenance of the myelin sheath. Depletion in sulfatide is a well-known characterization of Alzheimer's, even in early stages before it has been manifested as cognitive decline.

Microglia are the equivalent of white blood cells in the rest of the body. They are concerned with fighting off infective agents such as bacteria and viruses, and they also monitor neuron health, making life-and-death decisions: programming a neuron for apoptosis (intentional self-destruct) if it appears to be malfunctioning beyond hope of recovery, or is infected with an organism that is too dangerous to let flourish. It is especially the field of the microglia where a lot of present attention is directed since they appear to play such a crucial role in the defence of the CNS.

Professor Douglas Fields: ''Now is a pivotal moment in neuroscience. Scientific revolutions often erupt suddenly from a shift in perspective. Just as the startling realization that the Earth is not the center of the universe, it may not be correct to view neurons as the center of brain function. Pioneering neuroscientists are beginning to see the cellular basis of brain function as a partnership between cells that use electricity to communicate rapidly (neurons) and others (glia) that do not. Neither cell functions alone.'' (1)

Research has shown that glia cells cannot only sense neuronal activity, they can also control it. The microglia especially play a central role in brain injury and disease. They are almost certainly involved in the root cause in the development of the various brain disorders like Alzheimer's. In fact, more and more research is discovering that there is not much in our central nervous system where the glia are not involved. This discovery could be a pivotal moment in neuroscience (Fields), maybe it is not correct to see the neurons as the center of the brain function.

One reason why neuroscientists missed the glial connection was because they used the wrong tools for the job. Probing electrodes don't work with glia. Not until the 80's when they started using dyes did they become visible. And then the gigantic scope of the unknown began to emerge. Just counting the synapses at a rate of one per second would take 32 million years. And that would only be the beginning. Neurons are in fact outnumbered by the glial cells 3 to 1.

NOTE: Thanks to the Nissi staining technique cell in the 1880s they realized that microglia are related to macrophages. It was noted that the cells were found in a variety of viralbrain infections but they did not know what the clusters were. Pío del Río Hortega, a student of Santiago Ramón y Cajal, first called the cells "microglia" around 1920. He went on to characterize microglial response to brain lesions in 1927 and note the "fountains of microglia" present in the corpus callosum and other perinatal white matter areas in 1932. After many years of research Rio-Hortega became generally considered as the "Father of Microglia .

Biologists have known for decades that microglia respond to infection and brain trauma, or any kind of insult, by clearing away diseased or damaged tissue and releasing substances that stimulate repair. They are central for neuro protection and defence of the central nervous system against exo- and endogenous insults. But last year, a study of how eye–brain connectivity is established in developing mice, showed that microglia also prune back synapses and rewire neural connections in a healthy brain, depending on the individual's visual experience shortly after birth. (2)

Microglia provide immune surveillance and are mobilized in response to a variety of different diseases and injuries. They are the resident immune cells in the brain and spinal cord. Microglia contribute to CNS development by removing apoptotic(self destruct) neurones and shaping neuronal networks through synaptic stripping; loss of microglial function in embryo-genesis may be one of the primary mechanisms of neurodevelopmental disorders such as autism.

Autophagy, a cellular recycling process responsible for turnover of cytoplasmic contents, is critical for maintenance of health. Defects in this process have been linked to diabetes. Diabetes-associated glucotoxicity/lipotoxicity contribute to impaired β-cell function and have been implicated as contributing factors to this disease.

At the early stages of neurodegenerative diseases including Alzheimer’s disease neuroglial cells become asthenic(weak) and lose some of their homoeostatic, neuroprotective, and defensive capabilities. Astroglial reactivity, for example, correlates with preservation of cognitive function in patients with mild cognitive impairment and prodromal (early symptom) Alzheimer’s disease (3)

Neuroscientists have known for several decades that glia 'cause' certain diseases. Nearly all cancers originating in the brain derive from glia (which, unlike mature neurons, undergo cell division). In multiple sclerosis, the myelin sheaths around axons become damaged, and in HIV-associated neurological conditions, the virus infects astrocytes and microglia, not neurons. But, and this a big but, although microglial activation is often considered neurotoxic, microglia are essential defenders against many neurodegenerative diseases and it is therefore more likely that weakened microglia, not being able to handle the defence properly, become damaged and thus part of the problem. It also seems increasingly likely that microglial dysfunction can underlie certain neurological diseases without an obvious immune component.

Dr. Streit:

''It is the microglial dysfunction hypothesis of Alzheimer’s disease (AD) claiming that neurofibrillary degeneration is the result of weakening microglial support.( publ.2010) The most visible, and until very recently, the only hypothesis regarding the involvement of microglial cells in Alzheimer's disease (AD) pathogenesis is centered around the notion that activated ( reactive ) microglia are neurotoxin-producing immune effector cells actively involved in causing the neurodegeneration that is the cause for AD dementia. The concept of detrimental neuroinflammation has gained a strong foothold in the AD arena and is being expanded to other neurodegenerative diseases.'' And this may be blaming the victim instead of the perpetrator.

Streit's review takes a comprehensive and critical look at the overall evidence supporting the neuroinflammation hypothesis and points out some weaknesses. His work also reviews evidence for an alternative theory, the microglial dysfunction hypothesis, which, although eliminating some of the shortcomings, does not necessarily negate the amyloid/neuroinflammation theory. The microglial dysfunction theory offers a different perspective on the identity of activated microglia and their role in AD pathogenesis taking into account the most recent insights gained from studying basic microglial biology.

In another study by Shakeel Mir and others at U.of Nebraska MC about Inhibition of Autophagy turnover: ''We tested the hypothesis that two conditions, glucotoxicity and lipotoxicity, affect β-cell function by modulating autophagy. We report that exposure of β-cell lines and human pancreatic islets to high levels of glucose and lipids blocks autophagic flux and leads to apoptotic cell death. EM(Electromagnetic) analysis showed accumulation of autophagy intermediates (autophagosomes), with abundant engulfed cargo in palmitic acid (PA)- or glucose-treated cells, indicating suppressed autophagic turnover. EM studies also showed accumulation of damaged mitochondria, endoplasmic reticulum distention, and vacuolar changes in PA-treated cells. (emphasis mine) Not being able to clear makes for a toxic mess!

Pulse-chase experiments indicated decreased protein turnover in β-cells treated with PA/glucose. Expression of mTORC1, an inhibitor of autophagy, was elevated in β-cells treated with PA/glucose. mTORC1 inhibition, by treatment with rapamycin, reversed changes in autophagic flux, and cell death induced by glucose/PA. Our results indicate that nutrient toxicity-induced cell death occurs via impaired autophagy and is mediated by activation of mTORC1 in β-cells, contributing to β-cell failure in the presence of metabolic stress (mammalian target of rapamycin complex 1 {mTORC1}or mechanistic target of rapamycin complex 1, is a protein complex that functions as a nutrient/energy/redox sensor and controls protein synthesis) (4)

Note: it is not difficult to see where this may be leading in the case of Alzheimer's

See further also:'' Cytotoxicity is enhanced when autophagy is blocked or severely reduced. An increasing number of studies have shown that autophagy is stimulated in response to external stressors (such as starvation and oxidative stress) and internal needs (for example, removal of aggregate-prone proteins). Autophagy is an evolutionarily conserved catabolic process responsible for the routine degradation of bulk superfluous or dysfunctional proteins and organelles.'' (5) It is almost certainly the principle behind the 'three-day fast'

In the face of all this it is not too outlandish to suggest that the concept introduced by Rudolf Virchof: Omnis cellula e cellula (everything comes from the cell) remains the fundamental principle of physiology and pathophysiology, which regards the dissection of cellular mechanisms as a main step in understanding and revealing the nature of the normal function and of the disease. The behaviour of individual cell types or even individual cells, and how they interact, are dependent on one another, becomes the main focal point of study.

However it is therefore also of utmost and singular importance that all players in this field are given their due, which might not have been the case in neurological studies which have up till now been far too neuronocentric. ''This neuronocentricity comes at odds with the intricate structure of the neural tissue formed by many types of cells of different origin, physiology, and functional specialization. These many cellular types exist in a state of continuous communication, which defines the functional outputs of the nervous system; similarly these heterogeneous cell populations and their interrelations represent the substrate for pathology''. (6)

Among all these multiple cell types, however, the neuroglia, being the main homoeostatic and defence element of the CNS assumes particular importance in evolution of neurological diseases.

There are aging-related morphological and phenotypic changes in rodent and human microglia that are consistent with both cell senescence and low-grade activation.

Alexei Verkhratsky Amelia Marutle et.al. : “...it is all but impossible to distinguish between low-grade neuroinflammatory and senescent changes and these seemingly contradictory phenomena are in fact one and the same. Since the focus is on aging when it comes to AD, it would be wise to stop using the term neuroinflammation as this is suggestive of pathology more severe than what really exists, and therefore potentially misleading. In the context of aging it makes sense to speak simply of microglial senescence, which in humans progresses to an advanced, pathological level, called dystrophy, that can be directly associated with neurofibrillary degeneration.”

Which of course immediately raises the question: what causes the senescence? Part of which we probably know already. Glia as opposed to neurons, can divide, multiply, which is a strength and a weakness. Cell division often comes at the cost of shortening telomeres.

As Streit already noticed: it is probably wrong to consider the microglia as aggressive immune effector cells, which is the unfortunate result of prematurely over interpreting and extrapolating in vitro observations, and this has not been helpful for advancing understanding of AD pathogenesis. Microglial cells are not aggressors; they are victims of free radical damage like all cells. To help curb the ongoing dementia epidemic a major scientific challenge for the future will be to find ways of slowing or minimizing microglial senescent degeneration.

In Parkinson's disease and Alzheimer's disease, over-activation of microglia may play an active role in the pathogenesis because microglia senescence primes them to be neurotoxic during the development of the diseases. Also having to deal with a continuous load of free radical damage, keeps the microglia in an overly excited, activated state, and the continuous dividing and producing new scavenger cells will undoubtedly have a detrimental effect on the life of a microglia cell.

(See also further down the conclusions of Flanary et.al.)

In a normal situation when brain injury or any insult that happens, microglia cells change their morphology dramatically, migrate to the lesion sites, and proliferate. Proliferated microglia cells phagocytose dying cells and other debris and/or release cytokines to maintain the micro environment homoeostasis and support injured neurons, and thus are beneficial for the neuronal survival.

Activated microglia are mainly scavenger cells but also perform various other functions in tissue repair and neural regeneration. They form a network of immune alert resident macrophages with a capacity for immune surveillance and control. Activated microglia can destroy invading micro-organisms, remove potentially deleterious debris, promote tissue repair by secreting growth factors and thus facilitate the return to tissue homoeostasis.

But if the glia have become weak because of whatever reason, they may not be able to tackle the job properly.

By using in vivo two-photon imaging techniques, Nimmerjahn et al. found that in the healthy, intact brain microglia are actually highly active and survey their microenvironment continually with extremely motile processes and protrusions. The same study also suggests that activated microglia exert a neuroprotective role by shielding the injured sites and phagocytosing damaged tissue. Since micro-damages may happen frequently throughout the CNS due to microischemic events or accumulated metabolic products, or even degenerating neurons, it is conceivable that microglia are constantly activated and, in most cases, respond to these micro-damages in a neurotrophic fashion. (7)

As the sentinel and essential cells of the CNS, microglia are not supposed to be harmful to the neuron. However, if the microglia activation in the brain oversteps the threshold of tolerability, it might contribute to pathology rather than have a sentinel or defensive role. Even though this contribution may be just the extra accumulation of debris.(8)

Concrete and valid proof of neuroprotection of the activated microglia may be lacking, there are studies that provide strong evidence demonstrating the neurotrophic (healing) work of activated microglia.

Activated microglia can also clear glutamate without evoking inflammatory mediators after traumatic injury and thus reduce neurotoxicity. It is this ability of the microglia to remove glutamate that has come under close scrutiny as being impaired by the presence of glyphosate.

Microglia have been demonstrated to protect neurons against ischemia either by synthesis of tumor necrosis factor (TNF alpha, a cytokine) or by engulfment of harmful invading neutrophil granulocytes. The protective roles of activated microglia have also been extensively discussed in multiple sclerosis (MS). All of the above studies provide strong evidence that activated microglial cells help injured neurons recover and that microglia is strongly indicated as beneficial to neuron survival. Therefore, activation of microglia is generally more beneficial than detrimental . . . . if the microglia is working normally. (10, 11, 12)

An important question is whether there are any other factors in addition to over activation and aging itself that could promote or delay microglia dysfunction in the aged brain. Are the age-related alterations in microglia function and morphology resulting from intrinsic or extrinsic factors? Does microglia over-activation and malfunction in the aged brain come from their failure to respond correctly to their microenvironment, or from an overloaded toxic microenvironment? Yet, it has been demonstrated that fully functional myeloid dendrite cells can be generated in vitro from blood monocytes from aged donors suggesting that there is no age-associated intrinsic defect in this lineage and that the age-related changes in macrophage function may be reversible with the proper environment and stimulation. (13)

Isolated microglia cells from aged brains exhibit decreased process complexity, altered granularity, and increased basal cytokines as compared to those from the young brain, suggesting an elevated inflammatory state in the aged microglia. However, after being stimulated with LPS (inflammatory), the fold-over-basal LPS response remains constant across ages, indicating a comparable inflammatory response machinery in aging microglia to that of young ones. These observations suggest that microglia dysfunction in the aged brain might be more related to the extrinsic events than intrinsic ones. (14) The notion that extrinsic rather than intrinsic factors are the major determinants for microglia's function is also supported by the regional differences in microglia. It has been shown that in different regions of the brain, microglia activation shows differential phenotypes.(ways of showing)

One possibility that is being considered is that there is a connection between microglia senescence and the amyloid plaque. Studies have shown that amyloid deposition is associated with mitochondrial dysfunction and a resulting generation of reactive oxygen species(ROS), which can initiate a signalling pathway leading to apoptosis. However it has as yet not been established what the exact connection is. Is the plaque there because of the failure of the senescent glia to respond?

Cell-autonomous or cell-non-autonomous

Cell-autonomous mechanisms (i.e., those in which the plaques act directly on the neurons that will ultimately die, which are the same cells that produced the Aß and tau protein that make up the plaques) are likely to be most important, but some scholars have begun to consider the cell-non-autonomous possibilities. What if the primary action of amyloid plaques is on another type of cell entirely - such as the ubiquitous, essential, yet still poorly understood neuronal support cell- the microglia?

Flanary et. al. argue that the presence of amyloid plaques accelerates the process of microglial senescence: “.. Advanced age and presence of intracerebral amyloid deposits are known to be major risk factors for development of neurodegeneration in Alzheimer’s disease (AD), and both have been associated with microglial activation. However, the specific role of activated microglia in AD pathogenesis remains unresolved. Here we report that microglial cells exhibit significant telomere shortening and reduction of telomerase activity with normal aging in rats, and that in humans there is a tendency toward telomere shortening with presence of dementia. Human brains containing high amyloid loads demonstrate a significantly higher degree of microglial dystrophy than non-demented, amyloid-free control subjects. Collectively, these findings show that microglial cell senescence associated with telomere shortening and normal aging is exacerbated by the presence of amyloid. They suggest that degeneration of microglia is a factor in the pathogenesis of AD. '' Telomeres, the repeated sequences that cap chromosome ends, undergo shortening with each cell division, and therefore serve as markers of a cell's replicative history. In vivo, clonal expansion of T cells during immune responses to both foreign and auto-antigens is associated with telomere shortening In fact the ability to divide and transform as needed in defence of the CNS could be its Achilles heel. In other words the microglia can, with extreme overloads in free radicals, reactive oxygen species, be worn threadbare and not function anymore as they should.

It deserves repeating that weakened or dying microglia have been discovered before symptoms of degeneration have become evident. (29)

Note: This true for all T cells throughout the system. See also: “immune responses become compromised during ageing. Age-related defects including both the relatively low number and the dysfunction of aged T cells, appear to not only increase cancer incidence in later life, but also to decrease the effectiveness of immunotherapy to mount T-cell responses against cancers, which leads to high morbidity and mortality in the elderly population”

There could be a meaningful use of supplementation with Vit. E. Vitamin E is the most biologically active fat-soluble antioxidant, capable of neutralizing free radical damage to unsaturated fatty acids and therefore contributes to membrane stability and proper function !! “Age-Associated Decline in Effective Immune Synapse Formation of CD4 T Cells Is Reversed by Vitamin E Supplementation “ (16)

Consistent with this, senescent cells can be observed in amyloid brains, at higher levels than one would expect as a result of chronological age alone.

If it turns out that both neurons and glia are badly affected by the increasing presence of the plaque, there are two things to consider. First we see the inability of the microglia to respond in a normal matter, clearing the plaque. And secondly the origins of the plaque development.

In effect both may have the same origin: mitochondrial dysfunction, which can result in high levels of reactive oxygen species (ROS) and also rob the cell of energy it needs for maintenance of homoeostasis. Hauptmann et.al. report that in an AD mouse model, mitochondrial dysfunction can be observed very early in the progression of the disease: Indeed, mitochondria begin to exhibit respiratory-chain defects well before extracellular plaques can be observed.

Hauptmann:”Recent evidence suggests mitochondrial dysfunction as a common early pathomechanism in Alzheimer’s disease integrating genetic factors related to enhanced amyloid-beta (Aß) production and tau-hyperphosphorylation with aging, as the most relevant sporadic risk factor. '' (sporadic as opposed to familial)

It makes sense then to assume that the neurinflammatory theory might not have much of a leg to stand on, but on the contrary offer an alternative hypothesis of AD pathogenesis:

(1) the notion that microglia are neuron-supporting cells and neuroprotective; (2) the fact that development of non-familial, (sporadic AD) is inextricably linked to aging and/or extreme and continuous free radical damage.

It may therefore be rather the loss of neuroprotection rather than induction of microglia activation, that contributes to onset of the degeneration leading to the disease. (18, 19, 20)

At present it is believed that microscopically visible protein aggregates, which are frequently associated with neurodegenerative diseases, in fact play a cytoprotective role, while toxicity of amyloidogenic proteins is related to accumulation of their oligomeric species (clumping together)

It has been reported that Amyloid beta impairs mitochondrial redox activity and increases the generation of reactive oxygen species (ROS). Several studies also suggest that A.beta-induced oxidative stress leads to apoptotic neuronal cell death that can be inhibited by antioxidants. Nitric oxide (NO) synthesized by NO synthases (NOSs) also appears to participate in the pathogenesis of AD. Pathologic studies have suggested a functional link between NO and AD, in that neurofibrillary tangles in AD brain contain inducible NOS and exhibit nitrotyrosine (which is an oxidative stress marker) formation in protein. This also affects neurofibrillary pathology.

No effect of anti-inflammatory drugs

The neurofibrillary degeneration that occurs in Alzheimer's disease (AD) is thought to be the result of a chronic and damaging neuroinflammatory response mediated by, either neurotoxic substances produced by activated microglial cells, or by the same reaction to a beginning demyelination of axons. This neuroinflammation hypothesis of AD pathogenesis has led to numerous clinical trials with anti-inflammatory drugs, none of which have shown clear benefits for slowing or preventing disease onset and progression. In other words inflammation may not be as heavily involved as was initially assumed. As we discovered before. It is more likely that a partial demyelination of the axons caused a neurotrophic response from activated microglia. but with advancing age microglial functioning may be deteriorating.

“ we were able to determine the extent of microglial dystrophy in regions already showing neurodegeneration as well as in regions that would have developed neurodegeneration if the subject had lived longer. The results demonstrate that microglial cells begin their structural deterioration before neurofibrillary pathology sets in. This is particularly evident during Braak stage III where widespread microglial cytorrhexis (cytoplasm cell death) is coincident with extensive tau pathology in the entorhinal region (loss of smell) but also present in the middle temporal gyrus which does not yet show neurodegenerative changes at this stage. These observations strongly suggest that microglial degeneration precedes the onset of neurofibrillary pathology and therefore support the hypothesis of a causal relationship between the loss of microglial structural integrity and the onset of neurodegeneration.

The aging aspect is most likely just another contributing and extremely complex, multifactorial process with deregulation of the immune system. A wide spectrum of changes occurs in both adaptive and innate immune systems, particularly in the myeloid lineage, including the microglia, in the aged brain. Many neurodegenerative diseases are age-related, and the neuroinflammation characteristic of chronic reactive microgliosis is thought to contribute to the age-related neurodegeneration. Whether microglia dysfunction is determined by their intrinsic changes or results from a response to altered environment in the aging process remains controversial. And whether aging itself should maybe considered as a disease related directly to dysfunctional mitochondria. Which leads us to consider what means we have at our disposal to lighten the load on them.

Mitochondrial dysfunctioning.

Dysfunction of mitochondria will result in oxidative stress which is one of the underlying causal factors for a variety of diseases including neurodegenerative diseases, diabetes, cardiovascular diseases, and cancer

Mitochondria are the main intracellular location for generating adenosine triphosphate (ATP), the fuel for a cell’s metabolic needs, and therefore are referred to as the power plants of the cell. Energy is stored in the form of phosphate bond and is released when ATP is hydrolysed to adenosine diphosphate (ADP) to meet the requirement of a number of energy demanding cellular processes.

However, mitochondria are far more than just power suppliers. They are also involved in many other cellular functions, including calcium signalling, heme and steroid synthesis, regulation of membrane potential, proliferation or apoptosis, and redox homeostasis maintenance, to name just a few. Because of all these activities mitochondria are the major sites for free radical species production, including both reactive oxygen species (ROS) and reactive nitrogen species (RNS), which on the positive side is indispensable for proper cell signalling; on the other hand, excessive generation of ROS results in cell/tissue injury and death.

In the past decade, more and more pieces of evidence are surfacing to point to the role of ROS as critical mediators of the balance between cell proliferation and cell death and the role of external or exogenous factors are getting more and closer scrutiny. However, this being in fact an area as vast and of such variety, it is almost certain to generate an incredible scala in options, means and ways to consider.

Yet, it should be possible to distinguish between at least two areas of interest. The one being nutrition as anti-inflammatory drugs providing the necessary stuff to keep things moving, and the other which we could call the supplementaries, which in most cases are there to aid the immune system. In most cases the two will be part of the same thing.

The nutrition part could be considered as a necessary evil, it will of necessity generate byproducts, stuff that isn't needed and has to be cleared out of the way. Too much of the wrong stuff can create congestion, and overload the system, cause extra inflammation etc. Creating a heavy demand on the scavenger cells. Microglia cells will divide on demand and as live transformers change from sentinel to scavenger. However every time a glia divides its telomeres get a little bit shorter and eventually they will run out of options. Keeping inflammation therefore at an absolute minimum is a must.

Since mitochondria are major sources for ROS production, it is not surprising that they are well equipped with antioxidant defences, including a large pool of glutathione, glutathione peroxidase, glutathione reductase, MnSOD, catalase, and the thioredoxin system.(Thioredoxins are proteins that act as antioxidants by facilitating the reductions of other proteins). Excessive levels of ROS will lead to protein oxidation and lipid peroxidation causing damage to mitochondrial membrane, proteins, and DNA, especially when the mitochondrial DNA is not protected with associated histones.

Researchers are only recently discovering that both fat and cholesterol are severely deficient in the Alzheimer's brain. It turns out that fat and cholesterol are both vital nutrients in the brain. The brain contains only 2% of the body's mass, but 25% of the total cholesterol. Cholesterol is essential both in transmitting nerve signals and in fighting off infections.

Yeon-Kyun Shin is an expert on the physical mechanism of cholesterol in the synapse to promote transmission of neural messages, and one of the authors of referenced earlier. In an interview by a Science Daily reporter, Shin said: "If you deprive cholesterol from the brain, then you directly affect the machinery that triggers the release of neurotransmitters. Neurotransmitters affect the data-processing and memory functions. In other words -- how smart you are and how well you remember things." Or . . . . . statin drugs could really make you dumb. A common side effect of statins is memory dysfunction.

Taking all this into account, it may not be such a good idea to have statin drugs interfere with the production of cholesterol in the liver and in the process the production of Co-enzyme Q10, specifically produced to function as an antioxidant to protect, among other things, cholesterol on its way from the liver to the brain and other cells.

As can be gleaned from the aforementioned, low saturated fat, low cholesterol and a high inflammation load appear to be at the root of a cascade of issues, all affecting brain functioning.

Since mitochondria are fundamental energy generators, severe damage to mitochondria will inevitably cause disorders in cellular functions and as one of the major ROS producers within the cell, have been rendered susceptible to oxidative damage when the antioxidant defence machinery fails to meet their ROS scavenging tasks; therefore, they are implicated in the pathology of various diseases including neurodegenerative diseases, diabetes, cardiovascular diseases, and cancer.

So what about the amyloid Beta plaques?

Well that story is a little more complicated.

Most cell types can use either fats or glucose (from carbohydrates) as a fuel source to satisfy their energy needs. However, the brain is the one huge exception to this rule. All cells in the brain, both the neurons and the glial cells, are unable to utilize fats for fuel. This is likely because fats are too precious to the brain. The myelin sheath requires a constant supply of high quality fat to insulate and protect the enclosed axons. Since the brain needs its fats to survive long-term, it is paramount to protect them from oxidation (by exposure to oxygen) and from attack by invasive microbes.

It turns out that, although apoE is not found in LDL, it does bind to LDL, and this means that astrocytes can unlock the key to LDL and hence the cholesterol and fatty acid contents of LDL are accessible to astrocytes as well, as long as apoE is functioning properly. The astrocytes reshape and repackage the lipids and release them into the cerebospinal fluid, both as B(rain)-HDL and simply as free fatty acids, available for uptake by all parts of the brain and nervous system.

One of the critical reshaping steps is to convert the fats into types that are more attractive to the brain. The brain works best when the constituent fats are long, and, indeed, the astrocytes are able to take in short chain fats and reorganize them to make longer chain fats.

An astrocyte needs a significant energy source to synthesize fats and cholesterol, and this energy is usually supplied by glucose from the blood stream. Furthermore, the end-product of glucose metabolism is acetyl-Coenzyme A, the precursor to both fatty acids and cholesterol. Glucose can be consumed very efficiently in the mitochondria, internal structures within the cell cytoplasm, via aerobic processes that require oxygen. The glucose is broken down to produce acetyl-Coenzyme A as an end-product, as well as ATP, the source of energy in all cells. But! oxygen is toxic to lipids (fats), because it oxidizes them. Lipids are fragile if not encased in a protective shell like HDL, or LDL. Once they are rancid they are susceptible to infection by invasive agents like bacteria and viruses. So an astrocyte trying to synthesize a lipid has to be very careful to keep oxygen out, yet oxygen is needed for efficient metabolism of glucose, which will provide both the fuel (ATP) and the raw materials (acetyl-Coenzyme A) for fat and cholesterol synthesis. So what to do?

There is an alternative, although much less efficient, solution: to metabolize glucose anaerobically directly in the cytoplasm. This process does not depend on oxygen but it also yields substantially less ATP (only 6 instead of 30 if glucose is metabolized aerobically in the mitochondria). The end product of this anaerobic step is a substance called pyruvate .

Pyruvate or pyruvic acid supplies energy to living cells through the citric acid cycle when oxygen is present, and alternatively ferments to produce lactate when oxygen is lacking (fermentation).

Pyruvate could be further broken down to yield a lot more energy, but this process is not accessible to all cells, and it turns out that the astrocytes need help for this to happen, which is where amyloid-beta comes in. Amyloid-beta has the unique capability of stimulating the production of an enzyme, lactate dehydrogenase, which promotes the breakdown of pyruvate into lactate, through an anaerobic fermentation process, rejuvenating NAD+ and enabling the further production of a substantial amount of ATP through additional glycolysis.

The lactate, in turn, can be utilized itself as an energy source by some cells, and it has been established that neurons are on the short list of cell types that can metabolize lactate.

Seneff : “It is also known that apoE can signal the production of amyloid-beta, but only under certain poorly understood environmental conditions. I suggest those environmental triggers have to do with the internal manufacture of fats and cholesterol as opposed to the extraction of these nutrients from the blood supply. i.e., amyloid-beta is produced as a consequence of environmental oxidative stress due to an inadequate supply of fats and cholesterol from the blood.

In addition to being utilized as an energy source by being broken down to lactate, pyruvate can also be used as a basic building block for synthesizing fatty acids. So anaerobic glucose metabolism, which yields pyruvate, is a win-win-win situation: 1. it significantly reduces the risk of exposure of fatty acids to oxygen, 2. it provides a source of fuel for neighbouring neurons in the form of lactate, and 3. it provides a basic building block for fatty acid synthesis. But it depends upon amyloid-beta to work. Thus, in my view (and in the view of others, amyloid-beta is not a cause of Alzheimer's, but rather a protective device against it.” (Seneff)

“an increasingly vocal group of investigators are arriving at an “alternate hypothesis” stating that amyloid-β, while certainly involved in the disease, is not an initiating event but rather is secondary to other pathogenic events. Furthermore and perhaps most contrary to current thinking, the alternate hypothesis proposes that the role of amyloid-β is not as a harbinger of death but rather a protective response to neuronal insult” ( Dr. Mark A. Smith)

''Contrary to common concepts, the brain in Alzheimer's disease (AD) does not follow a suicide but a rescue program . . . . .preserve glucose for anabolic needs and promote the oxidative utilization of ketone bodies. The agent mediating the metabolic switch is soluble A-beta which inhibits glucose utilization and stimulates ketone body utilization at various levels. '' (Heininger) (21) Veech (30)

Pesticide Load

The latest attack on our mitochondria has been in the form of the slow eroding of its mineral supply needed for the enzymatic process and the shikimate pathway by the modern increased use of pesticides among which glyphosate stands out as one of the worst since it is known as a chelator, it binds minerals. It was patented to do just that. (US Patent number 7,771,736 B2. Glyphosate formulations and their use for the inhibition of 5-enolpyruvylshikimate-3-phosphate synthase.)

Just to give an example of how dangerous it is to mess with our enzymatic pathway, any malfunction (mutation, overproduction, underproduction or deletion) of a single critical enzyme can lead to a genetic disease. The malfunction of just one type of enzyme out of the thousands of types present in the human body can be fatal. Life simply is not possible without enzymes.

Dr. Seneff: “Manganese for instance is a catalyst for that very enolpyruvylshikimate phosphate synthase (EPSPS), a critical early enzyme in the pathway and deficiency can explain many of the pathologies associated with autism and Alzheimer’s disease (AD). The incidence of both of these conditions has been increasing at an alarming rate in the past two decades, in step with the increased usage of glyphosate on corn and soy crops. Although correlation does not necessarily mean causation, from 1995 to 2010, the autism rates in first grade in the public school correlates almost perfectly (P = 0.997) with total glyphosate application on corn and soy crops over the previous 4 years (from age 2 to 6 for each child). Such remarkable correlation certainly should be a cause for concern necessitating further experimental investigation. “

In fact there are multiple pathways by which glyphosate could lead to pathology. A major consideration is that our gut bacteria also have the shikimate pathway, and that we depend upon this pathway in our gut bacteria as well as in plants to supply us with the essential aromatic amino acids, tryptophan, tyrosine, and phenylalanine. Methionine, an essential sulphur containing amino acid, and glycine, are also negatively impacted by glyphosate. Furthermore, many other biologically active molecules, including serotonin, melatonin, melanin, epinephrine, dopamine, thyroid hormone, folate, coenzyme Q10, vitamin K, and vitamin E, depend on the shikimate pathway metabolites as precursors. Gut bacteria and plants use exclusively the shikimate pathway to produce these amino acids. In part because of shikimate pathway disruption, our gut bacteria are harmed by glyphosate, as evidenced by the fact that it has been patented as an antimicrobial agent.

Note: Glyphosate is a likely cause of the recent epidemic in celiac disease. Glyphosate residues are found in wheat due to the increasingly widespread practice of staging and desiccation of wheat right before harvest. Many of the pathologies associated with celiac disease can be explained by disruption of CYP enzymes.

Manganese (Mn) is an essential metal found in a variety of biological tissues and is necessary for normal functioning of a variety of physiological processes including amino acid, lipid, protein and carbohydrate metabolism. Mn also plays an essential role in immune system functioning, regulation of cellular energy, bone and connective tissue growth and blood clotting. In the brain, Mn is an important co-factor for a variety of enzymes, including the anti-oxidant enzyme super-oxide dismutase, as well as enzymes involved in neurotransmitter synthesis and metabolism. And as is always the case too much or too little is both detrimental.

Mn deficiency as well as excess is due to glyphosate interference. Because of glyphosate’s disruption of CYP enzymes, the liver becomes impaired in its ability to dispose of Mn via the bile acids, and instead it transports the Mn via the vagus nerve to brain-stem nuclei, where excess Mn leads to PD. Recently, PD has also increased dramatically, in step with glyphosate usage on corn and soy. So ironically, while the brain-stem suffers from excess Mn, the rest of the brain incurs Mn deficiency due to the depressed serum levels of Mn.

Mn is particularly important in the hippocampus, and deficiency there can lead to seizures. A high incidence of seizures is found in children with autism. Seizures are also associated with reduced serum Mn, and this is consistent with the liver’s inability to distribute Mn to the body via the bile acids.

And if that wasn't bad enough, glyphosate is also neurotoxic. Its metabolism in us (and all mammals) yields two products: Aminomethylphosphonic acid (AMPA) and glyoxylate, with AMPA being at least as toxic as glyphosate. Glyoxylate is a highly reactive glycating agent, which will disrupt the function of multiple proteins in cells that are exposed. Glycation has been directly implicated in Parkinson’s disease (PD). Glyphosate has been detected in the brains of malformed piglets. In a report produced by the Environmental Protection Agency (EPA), over 36% of 271 incidences involving acute glyphosate poisoning involved neurological symptoms, indicative of glyphosate toxicity in the brain and nervous system.

Everything and worse can be read in the latest update from Seneff and Samsel : Glyphosate, pathways to modern diseases III (23)

Biocides, such as herbicides, are routinely tested for toxicity but not for sub-lethal effects on microbes. Many biocides are known to induce an adaptive multiple-antibiotic resistance phenotype. And that could constitute a much bigger problem down the road, if it means that medical interventions involving surgical procedures cannot be entertained anymore because of resistant microbes.(24)

Another attack has been in the form of adjuvants in the vaccines. The worst probably being aluminum and mercury, both well known neurotoxins . . Two-month old babies now receive 1,225 mcg of aluminum from their vaccines -- 50 times higher than safety levels! Although the FDA, CDC and World Health Organization are aware of the dangers, they expect parents to play Russian roulette with their children. The excuse that we get more mercury from fish is of course a lame one, since there is quite a difference between orally ingesting and vaccinating it straight into the blood stream.

Healthy mitochondria

From what we have learned so far it seems to be wise to not bite hand that feeds you, which is what we seem to be doing continually with the way we live, the way we grow and process our food, etc. Since it is the billions of mitochondria that feed us, we'd better take good care of them. Prevent them from getting harmed, feed them the right stuff and aid them in any way possible to lighten the load.

And that's when all hell breaks loose.

At this point even the most conscientious nutrition scientists often become like theologians who have discovered the true religion and refuse to consider alternative options. We may have pretty much laid to rest the fat and cholesterol disease causing theory, scientific proof of one or the other is often hard to get since there are always more things to consider and allow for.

Also it is sometimes very difficult to believe that the scientists in a certain study were not more concerned with proving a certain hypothesis, than with actually finding the truth.

Amyloid (A)Beta pathology and cognitive deficits are exacerbated by a high-fat diet (Julien et al., 2010) in mouse models of AD”. (Kapogiannis and Mattson, 2011; Xu et al., 2011) . . . Right! Mice are just furry little humans? Actually mice metabolize fat differently than humans. And all fats are the same?? and do we know what fats were used? The standard fare in tests in an industrial concoction.

Persons with high intake of polyunsaturated fatty acids (PUFAs) have lower cardiovascular morbidity and mortality. The protective effect of PUFAs is mediated by multiple mechanisms, including their antiinflammatory properties.'' Ferruci et.al. . http://www.ncbi.nlm.nih.gov/pubmed/16234304/

Right! unless you study the paper and discover a half truth and a half untruth. In fact the Omega 6 PUFAs are highly inflammatory, while the Omega 3 PUFAs are not.

In the present day context where the relationship between N-3 and n-6 is completely out of wack, this poses a serious problem.. Where a healthy ratio would be 1 : 1 or at most 1 : 2, the reality is more 1 : 10 all the way op to 20.

As mentioned before, it is often very difficult to establish what kind of fat is being used. Often fat from animal sources are considered saturated while in most cases nearly half of it is polyunsaturated and if from concentrated animal feeding operations(CAFOs) the unsaturated is high in Omega 6 (grainfed). Consequently what is being measured is not the effect of saturated fat but that of polyunsaturated of the wrong kind.

Calorie restriction

Another approach to a mitochondria friendly diet would be a calorie restricted one.

'' Caloric restriction (CR) without malnutrition increases longevity and delays the onset of age-associated disorders in short-lived species, from unicellular organisms to laboratory mice and rats.''

''Caloric restriction (CR) is one of the most robust interventions shown to delay ageing in diverse species from yeast to mammals. Reduced calorie intake without malnutrition extends lifespan in rodents and delays the onset of multiple age-associated diseases '' (26, 27)

''It is widely accepted that caloric restriction (CR) without malnutrition delays the onset of aging and extends lifespan in diverse animal models including yeast, worms, flies and laboratory rodents. The mechanism underlying this phenomenon is still unknown ''

Even if a number of researchers come to the conclusion that calorie restriction works to delay aging, most if not all indicate they don't know the underlying mechanism, yet, if we remind ourselves of the life and work of the microglia and how any insult or trauma or whatever, causes the microglia to get into action and divide and go to work, it is not difficult to understand that we will eventually wear them out prematurely and thus be exposed to a variety of insults without the full protection where it counts.

And then of course there are the multiple assaults we all encounter in our everyday life, some of which affect the life and work of our mitochondria direct. It's the air we breathe, the stuff we put on our skin, and the stressful lives we often live.

Conclusion:

Diet:

A healthy diet would most likely be anything that resembles the diet that has brought us here.

A diet rich in healthy fats, plant (avocado, olive, coconut) as well as animal (seafood, beef, chicken and pork) and carbohydrates mostly from vegetables.

Moderate intake in meat. A diet higher in healthy fats than carbohydrates. And possibly even more moderate in pork, since not many pigs are raised on pasture. Lots of grain creating the wrong kind of polyunsaturated fats

Avoid all modern grains in whatever shape or form because all of them have glyphosate. And if grains, always organic, unless from a farmer you trust not to spray glyphosate. Actually all your vegetables should be pesticide/chemical free, so that you don't have to wash them. They come with a healthy load bacteroidetes, the good guys that help building a healthy gut. (28)

If it comes in a package it should be suspect. Real food does not need packaging. Except when frozen. With our food often travelling the globe before it reaches our plate, the loss of nutrients can be staggering. Flash frozen is almost always fresher than fresh.

There is no real food that can be trusted in the center aisles of the grocery store.

All seed oils are a direct attack on our mitochondria because the toxic load of Omega 6.

Most crackers, chips etc. have been produced with deodorized rancid oxidized polyunsaturated fats.

The only sugars that can be trusted in limited amounts are the ones bound up in the fruit and plant fibres and the ones that come in the form of wild honey and maple syrup (without is probably better)

Supplements

If you have access to a good supply of healthy fresh foods you should not need a lot of supplements. In winter you may want to add Vitamin D and C. There are heavy losses of C in transport and D because of loss of sun exposure.

Flu and colds surface in late fall and winter and has nothing to do with cold weather and everything with running out of both C and D.

We usually don't eat enough seafood therefore add Omega 3.

The only mineral you possibly need is magnesium, one of the most abundantly used minerals in the body. But just as in the case with calcium and iron (two other important ones) it is always better to get them from your diet. Calcium supplements actually can become a health hazard very quickly.

Most vegetables will come with all the antioxidants, polyphenols and anthocyanins you need to assist your mitochondria. Of special interest has been curcumin, now being tested for anticarcinogenity.

Also there has been increasing interest in Epigallocatechin-3-Gallate (EGCG)

EGCG is the most abundant polyphenol found in green tea. Apart from its iron-chelating property, the antioxidant capacity of EGCG has been demonstrated at the level of mitochondria where it not only enhances the activities of both TCA cycle (citric acid) enzymes and ETC (electron transfer) complexes but also upregulates the antioxidant system in aged brain. (31)

The body produces a healthy load of antioxidants, however when getting older this production might need some help. Melatonin is produced mainly during sleep but less so when getting older. The same holds for Co-enzyme Q10. Both are of utmost importance when the aging body is producing more free radical activity.

Note: The lipoproteins that carry the fatty acids and esterified cholesterol along with certain antioxidants that are conveniently being transported to the cells packaged in the same cargo ship. Esterification is a technique to render the fats and cholesterol inert, which helps protect them from oxidation. Having the antioxidants (such as vitamin E and Coenzyme Q10) along for the ride is also convenient, as they too protect against oxidation.

Statins interfere with a crucial intermediate step on the pathway to the synthesis of both cholesterol and coenzyme Q10. Coenzyme Q10 is also known as "ubiquinone" because it seems to show up everywhere in cell metabolism. It is found both in the mitochondria and in the lysosomes (cell's waste disposal system), and its critical role in both places is as an antioxidant

Lifestyle

Get enough sleep. One of your best antioxidants (melatonin) is created while you are sleeping. Also when you are sleeping your immune system is hard at work to clean up the daily mess. And sleep in a darkened room.

Stress is a free radical creator. Learn to practice meditation in whatever shape or form. Yoga is a form of meditation.

Move your DNA. While a lot of people simply have no other choice than to sit all day, you have many ways of breaking it up, exercising. Standing up from a sitting position equals a five minute walk. Standing up from a squatting position is even better.

When sitting, don't hunch, keep your shoulders back. When walking, do the same. You may find the odd quarter when hunched but it ain't worth it., and park your car further away from the entrance of the mall, and take the stairs.

Start every day with a smile, whether you feel to it or not. Smile when you're cut off in traffic. Smile when you hammer your thumb.

It has an incredible positive effect on the upper part of your body, but if done well you'll be able to feel it in your gut.

Relax your neck muscles at the same time.

Get at least some outside time every day.

Prepare the family meals together. enjoy the family meals together.

Get the kids involved in looking for different ways to prepare the Brussels sprouts.

Get sun exposure to get your vitamin D. And take a cue from your goat. They make more than 10,000mg of Vitamin C per day.

Brush your teeth with baking soda. If using toothpaste look for one without glycerin because you want you veggies to be able to remineralize your enamels. And you will never need a dentist.

Afterword: I realize that I have especially focused on a few nutrition related issues that are quite clearly at play. For instance apoE4, seen here as a risk factor doesn't appear to be as important in cultures that are quite different from our western fast food etc. life style. It appears apoE4 requires a hyperlipidaemic lifestyle to manifest as AD risk factor, which is what we often have connected with a low fat high refined carbohydrate diet.

But there are other things at play. A dysfunctional thyroid, as appears to be an increasing phenomenon in our society, certainly affects cerebral metabolism as well. The relevance of trace minerals is only mentioned in passing.

Dr. Kurt Heininger indicated: “ A variety of genetic, medical and environmental factors modulate the ageing-related processes leading the brain into the devastation of AD. In accordance with the concept that AD is a metabolic disease, these risk factors deteriorate the homeostasis of the Ca(2+)-energy-redox triangle and disrupt the cerebral reserve capacity under metabolic stress''.

The fact that increasingly we have to deal with hormonal imbalances. Only a small amount of hormone is required to alter cell metabolism. Endocrine hormone molecules are released directly into the bloodstream, whereas exocrine hormones are secreted directly into a duct, and, from the duct, they flow either into the bloodstream or from cell to cell by diffusion in a process known as paracrine signalling. Recently it has been found that a variety of exogenous modern chemical compounds have hormone-like effects on both humans and wildlife. Their interference with the synthesis, secretion, transport, binding, action, or elimination of natural hormones in the body are responsible of homeostasis, reproduction, development, and/or behavioural changes same way as the endogenous produced hormones. The effect on cerebral metabolism is not sourced.